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Title
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Design, synthesis and stepwise optimization of nitrile-based inhibitors of cathepsins B and L
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Author
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Abstract
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| Human cathepsin B (CatB) is an important biological target in cancer therapy. In this work, we performed a knowledge-based design approach and the synthesis of a new set of 19 peptide-like nitrile-based cathepsin inhibitors. Reported compounds were assayed against a panel of human cysteine proteases: CatB, CatL, CatK, and CatS. Three compounds (7h, 7i, and 7j) displayed nanomolar inhibition of CatB and selectivity over CatK and CatL. The selectivity was achieved by using the combination of a para biphenyl ring at P3, halogenated phenylalanine in P2 and Thr-O-Bz group at P1. Likewise, compounds 7i and 7j showed selective CatB inhibition among the panel of enzymes studied. We have also described a successful example of bioisosteric replacement of the amide bond for a sulfonamide one [7e -> 6b], where we observed an increase in affinity and selectivity for CatB while lowering the compound lipophilicity (ilogP). Our knowledge-based design approach and the respective structure-activity relationships provide insights into the specific ligand-target interactions for therapeutically relevant cathepsins. |
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Language
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English
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Source (journal)
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Bioorganic and medicinal chemistry. - Oxford
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Publication
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Oxford
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2021
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ISSN
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0968-0896
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DOI
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10.1016/J.BMC.2020.115827
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Volume/pages
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29
(2021)
, 15 p.
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Article Reference
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115827
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ISI
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000612171900010
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Pubmed ID
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33254069
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Medium
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E-only publicatie
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Full text (Publisher's DOI)
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